Detrimental or beneficial: Role of endothelial ENaC in vascular function

Abstract

In the past, it was believed that the expression of the epithelial sodium channel (ENaC) was restricted to epithelial tissues, such as the distal nephron, airway, sweat glands, and colon, where it is critical for sodium homeostasis. Over the past two decades, this paradigm has shifted due to the finding that ENaC is also expressed in various nonepithelial tissues, notably in vascular endothelial cells. In this review, the recent findings of the expression, regulation, and function of the endothelial ENaC (EnNaC) are discussed.The expression of EnNaC subunits is reported in a variety of endothelial cell lines and vasculatures, but this is controversial across different species and vessels and is not a universal finding in all vascular beds. The expression density of EnNaC is very faint compared to ENaC in the epithelium. To date, little is known about the regulatory mechanism of EnNaC. Through it can be regulated by aldosterone, the detailed downstream signaling remains elusive. EnNaC responds to increased extracellular sodium with the feedforward activation mechanism, which is quite different from the Na + self-inhibition mechanism of ENaC. Functionally, EnNaC was shown to be a determinant of cellular mechanics and vascular tone as it can sense shear stress, and its activation or insertion into plasma membrane causes endothelial stiffness and reduced nitric oxide production. However, in some blood vessels, EnNaC is essential for maintaining the integrity of endothelial barrier function. In this context, we discuss the possible reasons for the distinct role of EnNaC in vasculatures.

Rapid Shear Stress-dependent ENaC Membrane Insertion is Mediated by the Endothelial Glycocalyx and the Mineralocorticoid Receptor

“…From these data, we postulate that shear stress sensed by the eGC activates a signaling cascade leading to the rapid membrane insertion of ENaC via exocytotic pathways. This is in agreement with a recent study indicating that shear stress may cause deflections of the eGC that in turn is transmitted via N-glycans to αENaC [7] for review see [47].…”

Rapid shear stress-dependent ENaC membrane insertion is mediated by the endothelial glycocalyx and the mineralocorticoid receptor

“…From these data, we postulate that shear stress sensed by the eGC activates a signaling cascade leading to the rapid non-genomic membrane insertion of ENaC. This is in agreement with a recent study indicating that shear stress may cause deflections of the eGC that in turn is transmitted via N-glycans to αENaC [ 7 ]; for review, see [ 52 ].…”

Aldosterone-stimulated endothelial epithelial sodium channel (EnNaC) plays a role in cold exposure–induced hypertension in rats

“…These results revealed a mechanism that aldosterone-mediated increase in the expression and activation of EnNaC via the Sgk1/Nedd4-2 pathway ultimately leads to impairment of vasodilatation and is one of the important elements in CIH. However, we did not observe the multiple opening EnNaC channels as characterized in renal epithelial cells, even under the condition of high concentration of aldosterone, which could be due to the lower density of EnNaC expressed at the plasma membrane of MAECs, the loss of stimulatory factors, and the presence of intracellular molecules that inhibit EnNaC in intact cells ( Wang et al, 2009 ; Paudel et al, 2022 ; Zhang et al, 2022 ).…”